Process for preparing amic acid esters

ABSTRACT

The present invention provides a process for producing an amic acid ester represented by the following general formula (7) (wherein A is substituted or unsubstituted lower alkylene or the like; R 1  is substituted or unsubstituted lower alkyl or the like; and R 3  is hydrogen or lower alkyl), which process comprises reacting, in the presence of water, an amino acid represented by formula (1) with a halogenated carbonic acid ester represented by formula (2) (wherein X is halogen) to form an amide compound represented by formula (3), then reacting the amide compound with a halogenated carbonic acid ester represented by formula (4) (wherein R 2  is substituted or unsubstituted lower alkyl or the like; and X is halogen) to form, in the system, a mixed acid anhydride represented by formula (5), and reacting the mixed acid anhydride with an amine compound represented by formula (6) (wherein Het is substituted or unsubstituted heterocyclic).

TECHNICAL FIELD

The present invention relates to an improved process for producing anamic acid ester from an amino acid. More particularly, the presentinvention relates to a process for producing an amic acid ester usefulas an intermediate for agrochemicals, from an amino acid (a rawmaterial) easily industrially at a low cost.

BACKGROUND ART

A mixed acid carboxyanhydride process has been known for reaction of theacid moiety of an amic acid obtained from an amino acid (a rawmaterial), with other amine (Nobuo Izumiya et al., “Synthesis ChemistrySeries—Peptide Synthesis”, pp. 126 to 129, Oct. 30, 1970, Maruzen K.K.).

In this process, first, the amino group of an amino acid is reacted witha chlorocarbonic acid ester to synthesize an amide; then, the carboxylicacid moiety of the amide is reacted with a chlorocarbonic acid ester toform a mixed acid carboxyanhydride; and the mixed acid carboxyanhydrideis reacted with a corresponding amine to synthesize an intended product.

In the process, however, since the formation of the acidcarboxyanhydride is slow in the presence of water, the second reactionmust be conducted in a non-aqueous system using a water-free solvent.Therefore, the amide synthesized in an aqueous solvent in the firstreaction needs to be dehydrated. Moreover, the second reaction needs tobe conducted in a non-aqueous system as mentioned above. Accordingly,the process has a problem in that it is complicated for industrialoperation.

Moreover, the dehydration step required for the synthesized amidereduces the productivity per unit time, etc. and needs a longer time forheating of the reaction system, resulting in decomposition of intendedproduct, etc. and consequent reduction in yield. Therefore, the aboveconventional process has a problem in cost as well.

The present invention aims at providing a process for producing an amicacid ester useful as an intermediate for agrochemicals, from an aminoacid (a raw material) easily industrially at a low cost.

DISCLOSURE OF THE INVENTION

The above aim has been achieved by the following inventions [1] to [9].

[1] A process for producing an amic acid ester represented by thefollowing general formula (7):

(wherein A is a substituted or unsubstituted lower alkylene group, asubstituted or unsubstituted cycloalkylene group, a substituted orunsubstituted arylene group, a substituted or unsubstitutedcycloalkylalkylene group or a substituted or unsubstituted aralkylenegroup; R₁ is a substituted or unsubstituted lower alkyl group, asubstituted or unsubstituted cycloalkyl group, a substituted orunsubstituted aryl group, a substituted or unsubstituted cycloalkylalkylgroup, a substituted or unsubstituted aralkyl group, a substituted orunsubstituted heterocyclic group or a substituted or unsubstitutedheterocyclic alkyl group; and R₃ is a hydrogen atom or a lower alkylgroup), which process comprises reacting, in the presence of water, anamino acid represented by the following general formula (1):

(wherein A has the same definition as given above) with a halogenatedcarbonic acid ester represented by the following general formula (2):

(wherein R₁ has the same definition as given above and X is a halogenatom) to form an amide compound represented by the following generalformula (3):

(wherein A and R₁ have the same definitions as given above), thenreacting the amide compound with a halogenated carbonic acid esterrepresented by the following general formula (4):

(wherein R₂ is a substituted or unsubstituted lower alkyl group, asubstituted or unsubstituted cycloalkyl group, a substituted orunsubstituted aryl group, a substituted or unsubstituted cycloalkylalkylgroup, a substituted or unsubstituted aralkyl group, a substituted orunsubstituted heterocyclic group or a substituted or unsubstitutedheterocyclic alkyl group; and X is a halogen atom) to form, in thesystem, a mixed acid carboxyanhydride represented by the followinggeneral formula (5):

(wherein A, R₁ and R₂ have the same definitions as given above), andreacting the mixed acid carboxyanhydride with an amine compoundrepresented by the following general formula (6) or salt thereof:

(wherein R₃ has the same definition as given above and Het is asubstituted or unsubstituted heterocyclic group).

[2] A process for producing an amic acid ester, set forth in [1],wherein the amino acid represented by the general formula (1) isdissolved in water and reacted with the halogenated carbonic acid esterrepresented by the general formula (2).

[3] A process for producing an amic acid ester, set forth in [1],wherein the reaction of the amide compound represented by the generalformula (3) with the halogenated carbonic acid ester represented by thegeneral formula (4) is conducted in a reaction system comprising wateror a water-organic solvent mixture.

[4] A process for producing an amic acid ester, set forth in [1],wherein the reaction of the mixed acid carboxyanhydride represented bythe general formula (5) with the amine compound represented by thegeneral formula (6) or its salt is conducted in a reaction systemcomprising water or a water-organic solvent mixture.

[5] A process for producing an amic acid ester, set forth in [1],wherein all the steps are conducted in one pot (one reactor).

[6] A process for producing an amic acid ester, set forth in [1],wherein the amino acid represented by the general formula (1) is valineand the chlorocarbonic acid ester represented by the general formula (2)is isopropyl chlorocarbonate.

[7] A process for producing an amic acid ester, set forth in [6],wherein all the steps are conducted in one pot (one reactor).

[8] A process for producing an amic acid ester, set forth in [1],wherein the amino acid represented by the general formula (1) is anoptically active valine and the amine represented by the general formula(6) is an optically active 1-(6-fluorobenzothiazol-2-yl)ethylamine.

[9] A process for producing an amic acid ester, set forth in [8],wherein all the steps are conducted in one pot (one reactor).

The present inventors made a study in order to achieve the above aim. Asa result, the present inventors surprisingly found out that an amic acidester can be produced in one pot (one reactor) in the presence of waterby adding, to an amino acid (prepared in the form of an aqueous solutionof its alkali salt), a chlorocarbonic acid ester to form an amidecompound, as necessary neutralizing the alkali present in excess with anacid, adding thereto an organic solvent (e.g. toluene) and a catalyticamount of a tertiary amine to convert the reaction system into atwo-phase system, reacting further the amide compound with achlorocarbonic acid ester in the presence of water to form a mixed acidanhydride in the reaction system in the presence of water, and reactingthe mixed acid anhydride with an amine compound corresponding to theintended product (when the amine compound is in the form of a salt suchas hydrochloride, sulfonate or the like, an alkali is also added); andmoreover that when the raw materials used [for example, the amino acidrepresented by the above general formula (1) and the amine compoundrepresented by the above general formula (6)] are optically activecompounds, there can be synthesized an optically active amic acid esterin which the optical purities of the raw materials used aresubstantially retained. The above findings have led to the completion ofthe present invention.

BEST MODE FOR CARRYING OUT THE INVENTION

The process of the present invention is described in detail below.

First, description is made on the terms used in this specification.

The term “substituted or unsubstituted” referred to herein means thatthe group following the term may be unsubstituted or substituted with,for example, halogen atoms including fluorine atom, chlorine atom,bromine atom and iodine atom (hereinafter, “halogen atoms” have the samedefinition as above unless otherwise specified, and this applies toother substituents); C₁₋₆ straight or branched chain lower alkyl groupsincluding methyl group, ethyl group, n-propyl group, isopropyl group,n-butyl group, isobutyl group, sec-butyl group, tert-butyl group,n-pentyl group and n-hexyl group; hydroxyl group; lower alkoxy groups[(lower alkyl)-o-groups] wherein the alkyl moiety is the above-mentionedlower alkyl group, including methoxy group, ethoxy group, n-propoxygroup, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxygroup, tert-butoxy group, n-pentyloxy group and n-hexyloxy group; loweralkoxycarbonyl groups [(lower alkoxy) —CO—groups] wherein the alkoxymoiety is the above-mentioned lower alkoxy group; carbamoyl group[NH₂—CO—]; and lower alkylcarbamoyl groups [(lower alkyl)—NH—CO—groups]wherein the alkyl moiety is the above-mentioned lower alkyl group.

The substituted or unsubstituted lower alkylene group refers to a C₁₋₆straight or branched chain alkylene group which may be substituted with,for example, halogen atoms, lower alkyl groups, hydroxyl group, loweralkoxy groups, lower alkoxycarbonyl groups, carbamoyl group and loweralkylcarbamoyl groups. The position of each substituent and the positionof each bond may be any position. As specific examples, there can bementioned methylene group, ethylene group, n-propylene group,isopropylene group, n-butylene group, isobutylene group, sec-butylenegroup, tert-butylene group, n-pentylene group and n-hexylene group.

The substituted or unsubstituted cycloalkylene group refers to a C₃₋₆cycloalkylene group which may be substituted with, for example, halogenatoms, lower alkyl groups, hydroxyl group, lower alkoxy groups, loweralkoxycarbonyl groups, carbamoyl group and lower alkylcarbamoyl groups.The position of each substituent and the position of each bond may beany position. As specific examples, there can be mentionedcyclopropylene group, cyclopentylene group and cyclohexylene group.

The substituted or unsubstituted arylene group refers to an arylenegroup (e.g. phenylene, naphthylene or anthranylene) which may besubstituted with, for example, halogen atoms, lower alkyl groups,hydroxyl group, lower alkoxy groups, lower alkoxycarbonyl groups,carbamoyl group and lower alkylcarbamoyl groups. The position of eachsubstituent and the position of each bond may be any position. Asspecific examples, there can be mentioned phenylene group, 1-naphthylenegroup, 2-naphthylene group and 1-anthranylene group.

The substituted or unsubstituted cycloalkylalkylene group refers to aC₁₋₆ straight or branched chain alkylene group substituted with C₃₋₆cycloalkyl group, which may be substituted with, for example, halogenatoms, lower alkyl groups, hydroxyl group, lower alkoxy groups, loweralkoxycarbonyl groups, carbamoyl group and lower alkylcarbamoyl groups.The position of each substituent and the position of each bond may beany position. As specific examples, there can be mentionedcyclopropylmethylene group, cyclopropylethylene group,cyclohexylmethylene group and cyclopropylhexylene group.

The substituted or unsubstituted aralkylene group refers to anaralkylene group (e.g. benzylene group or phenylethylene group) whichmay be substituted with, for example, halogen atoms, lower alkyl groups,hydroxyl group, lower alkoxy groups, lower alkoxycarbonyl groups,carbamoyl group and lower alkylcarbamoyl groups. The position of eachsubstituent and the position of each bond may be any position. Asspecific examples, there can be mentioned benzylene group andphenylethylene group.

The substituted or unsubstituted lower alkyl group refers to a C₁₋₆straight or branched chain alkyl group which may be substituted with,for example, halogen atoms, lower alkyl groups, hydroxyl group, loweralkoxy groups, lower alkoxycarbonyl groups, carbamoyl group and loweralkylcarbamoyl groups. The position of each substituent and the positionof each bond may be any position. As specific examples, there can bementioned methyl group, ethyl group, n-propyl group, isopropyl group,n-butyl group, isobutyl group, sec-butyl group, tert-butyl group,n-pentyl group, n-hexyl group, hydroxymethyl group, hydroxyethyl group,methoxymethyl group, ethoxymethyl group, methoxycarbonylmethyl group,ethoxycarbonylmethyl group, carbamoylmethyl group, methylcarbamoylmethylgroup, ethylcarbamoylmethyl group, methylcarbamoylethyl group andethylcarbamoylethyl group.

The substituted or unsubstituted cycloalkyl group refers to a C₃₋₆cycloalkyl group which may be substituted with, for example, halogenatoms, lower alkyl groups, hydroxyl group, lower alkoxy groups, loweralkoxycarbonyl groups, carbamoyl group and lower alkylcarbamoyl groups.The position of each substituent and the position of each bond may beany position. As specific examples, there can be mentioned cyclopropylgroup, fluorocyclopropyl group, chlorocyclopropyl group,bromocyclopropyl group, iodocyclopropyl group, methylcyclopropyl group,ethylcyclopropyl group, hydroxycyclopropyl group, methoxycyclopropylgroup, ethoxycyclopropyl group, methoxycarbonylcyclopropyl group,carbamoylcyclopropyl, methylcarbamoylcyclopropyl group, cyclobutylgroup, fluorocyclobutyl group, chlorocyclobutyl group, bromocyclobutylgroup, iodocyclobutyl group, methylcyclobutyl group, ethylcyclobutylgroup, hydroxycyclobutyl group, methoxycyclobutyl group,ethoxycyclobutyl group, methoxycarbonylcyclobutyl group,carbamoylcyclobutyl group, methylcarbamoylcyclobutyl group, cyclobutenylgroup, fluorocyclobutenyl group, chlorocyclobutenyl group,bromocyclobutenyl group, iodocyclobutenyl group, methylcyclobutenylgroup, ethyl cyclobutenyl group, hydroxycyclobutenyl group,methoxycyclobutenyl group, ethoxycyclobutenyl group,methoxycarbonylcyclobutenyl group, carbamoylcyclobutenyl group,methylcarbamoylcyclobutenyl group, cyclopentyl group, fluorocyclopentylgroup, chlorocyclopentyl group, bromocyclopentyl group, iodocyclopentylgroup, methylcyclopentyl group, ethylcyclopentyl group,hydroxycyclopentyl group, methoxycyclopentyl group, ethoxycyclopentylgroup and cyclohexyl group.

The substituted or unsubstituted aryl group refers to an aryl group suchas phenyl group, toluyl group, xylyl group, cumenyl group, biphenylgroup, naphthyl group, anthranyl group or the like, which may besubstituted with, for example, halogen atoms, lower alkyl groups,hydroxyl group, lower alkoxy groups, lower alkoxycarbonyl groups,carbamoyl group and lower alkylcarbamoyl groups. The position of eachsubstituent and the position of each bond may be any position. Asspecific examples, there can be mentioned phenyl group, o-fluorophenylgroup, m-fluorophenyl group, p-fluorophenyl group, o-chlorophenyl group,m-chlorophenyl group, p-chlorophenyl group, o-bromophenyl group,m-bromophenyl group, p-bromophenyl group, o-iodophenyl group,m-iodophenyl group, p-iodophenyl group, o-toluyl group, m-toluyl group,p-toluyl group, o-xylyl group, m-xylyl group, p-xylyl group, o-cumenylgroup, m-cumenyl group, p-cumenyl group, o-hydroxyphenyl,m-hydroxyphenyl, p-hydroxyphenyl, o-methoxyphenyl, m-methoxyphenyl,p-methoxyphenyl, o-carbamoylphenyl, m-carbamoylphenyl,p-carbamoylphenyl, o-methylcarbamoylphenyl, m-methylcarbamoylphenyl,methylcarbamoylphenyl, 1-naphthyl group, 2-naphthyl group and1-anthranyl group.

The substituted or unsubstituted cycloalkylalkyl group refers to a C₁₋₆straight or branched chain alkyl group substituted with C₃₋₆ cycloalkyl,which may be substituted with, for example, halogen atoms, lower alkylgroups, hydroxyl group, lower alkoxy groups, lower alkoxycarbonylgroups, carbamoyl group and lower alkylcarbamoyl groups. The position ofeach substituent and the position of each bond may be any position. Asspecific examples, there can be mentioned cyclopropylmethyl group,fluorocyclopropylmethyl group, chlorocyclopropylmethyl group,bromocyclopropylmethyl group, iodocyclopropylmethyl group,methylcyclopropylmethyl group, 1,1-dimethylcyclopropylmethyl group,1,2-dimethylcyclopropylmethyl group, hydroxycyclopropylmethyl group,methoxycyclopropylmethyl group, ethoxycyclopropylmethyl group,methoxycarbonylcyclopropylmethyl group, methylcarbamoylcyclopropylmethylgroup, cyclopropylethyl group, cyclohexylmethyl group andcyclopropylhexyl group.

The substituted or unsubstituted aralkyl group refers to an aralkylgroup (e.g. benzyl group, 1-phenylethyl group, 2-phenylethyl group,1-phenylpropyl group, 2-phenylpropyl group, 3-phenylpropyl group ornaphthylmethyl group) which may be substituted with, for example,halogen atoms, lower alkyl groups, hydroxyl group, lower alkoxy groups,lower alkoxycarbonyl groups, carbamoyl group and lower alkylcarbamoylgroups. The position of each substituent and the position of each bondmay be any position. As specific examples, there can be mentioned benzylgroup, o-fluorophenylmethyl group, m-fluorophenylmethyl group,fluorophenylmethyl group, 2,3-difluorophenylmethyl group,2,4-difluorophenylmethyl group, 2,5-difluorophenylmethyl group,3,4-difluorophenylmethyl group, 2,3,4-trifluoro-phenylmethyl group,2,3,5-trifluorophenylmethyl group, 3,4,5-trifluorophenylmethyl group,o-chlorophenylmethyl group, m-chlorophenylmethyl group,p-chlorophenylmethyl group, 2,3-dichlorophenylmethyl group,2,4-dichlorophenylmethyl group, 2,5-dichlorophenylmethyl group,3,4-dichlorophenylmethyl group, 2,3,4-trichlorophenylmethyl group,2,3,5-trichlorophenylmethyl group, 3,4,5-trichlorophenylmethyl group,o-bromophenylmethyl group, m-bromophenylmethyl group,p-bromophenylmethyl group, o-iodophenylmethyl group, iodophenylmethylgroup, p-iodophenylmethyl group, phenylethyl group, phenylethyl group,o-methylphenylmethyl group, m-methylphenylmethyl group,p-methylphenylmethyl group, 2,3-dimethylphenylmethyl group,2,4-dimethylphenylmethyl group, 2,5-dimethylphenylmethyl group,2-ethylphenylmethyl group, 3-ethylphenylmethyl group,4-ethylphenylmethyl group, o-(n-propyl)phenylmethyl group, m-(n-propyl)phenylmethyl group, p-(n-propyl)phenylmethyl group,o-(isopropyl)phenylmethyl group, m-(isopropyl)phenylmethyl group,p-(isopropyl) phenylmethyl group, o-hydroxyphenylmethyl group,m-hydroxyphenylmethyl group, p-hydroxyphenylmethyl group,methoxyphenylmethyl group, methoxyphenylmethyl group,p-methoxyphenylmethyl group, o-ethoxyphenylmethyl group,m-ethoxyphenylmethyl group, p-ethoxyphenylmethyl group,o-methoxycarbonylphenylmethyl group, m-methoxycarbonylphenylmethylgroup, p-methoxycarbonyl-phenylmethyl group, o-carbamoylphenylmethylgroup, m-carbamoylphenylmethyl group, p-carbamoylphenylmethyl group,o-methoxycarbamoylphenylmethyl group, m-methoxycarbamoyl-phenylmethylgroup and p-methoxycarbamoylphenylmethyl group.

The substituted or unsubstituted heterocyclic group refers to a 5- to10-membered single or condensed heterocyclic ring having, in the ring,at least one hetero atom selected from oxygen, nitrogen and sulfur, suchas pyridyl group, pyridazyl group, pyrimidyl group, pyrazinyl group,triazinyl group, pyranyl group, dioxanyl group, thianyl group, dithianylgroup, furyl group, oxolanyl group, dioxofuryl group, thienyl group,oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group,benzofuryl group, coumaranyl group, benzothienyl group, indolizinylgroup, benzoxazolyl group, benzothiazolyl group, chromenyl group,quinolinyl group, quinazolinyl group, quinoxalinyl group or the like,which ring may be substituted with, for example, halogen atoms, loweralkyl groups, hydroxyl group, lower alkoxy groups, lower alkoxycarbonylgroups, carbamoyl group and lower alkylcarbamoyl groups. The position ofeach substituent and the position of each bond may be any position. Asspecific examples of such a substituted or unsubstituted heterocyclicgroup, there can be mentioned pyridyl group, 2-fluoropyridyl group,4-chloropyridyl group, 2,4-dichloropyridyl group, 4-bromopyridyl group,4-iodopyridyl group, 2-methylpyridyl group, 4-ethylpyridyl group,2-hydroxypyridyl group, 2-methoxypyridyl group, 2-carbamoylpyridylgroup, 2-methylcarbamoylpyridyl group, pyridazyl group, pyrimidyl group,pyrazinyl group, 1,3,5triazinyl group, α-pyranyl group, β-pyranyl group,1,4-dithianyl group, furyl group, oxolanyl group, dioxofuryl group,dioxofuryl group, thienyl group, oxazolyl group, isoxazolyl group,thiazolyl group, isothiazolyl group, benzofuryl group, coumaranyl group,benzothienyl group, indolizinyl group, benzoxazolyl group,benzothiazolyl group, 2-fluorobenzothiazolyl group,4-fluorobenzothiazolyl group, 5-fluorobenzothiazolyl group,6-fluorobenzothiazolyl group, 7-fluorobenzothiazolyl group, 2H-chromenylgroup, 4H-chromenyl group, quinolinyl group, quinazolinyl group andquinoxalinyl group.

The substituted or unsubstituted heterocyclic alkyl group refers to aC₁₋₆ straight or branched chain alkyl group substituted with 5- to10-membered heterocyclic ring having, in the ring, at least one heteroatom selected from oxygen, nitrogen and sulfur (examples of the ring arepyridyl group, pyridazyl group, pyrimidyl group, pyrazinyl group,triazinyl group, pyranyl group, dioxanyl group, thianyl group, dithianylgroup, furyl group, oxolanyl group, dioxofuryl group, thienyl group,oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group,benzofuryl group, coumaranyl group, benzothienyl group, indolizinylgroup, benzoxazolyl group, benzothiazolyl group, chromenyl group,quinolinyl group, quinazolinyl group and quinoxalinyl group), which ringmay be substituted with, for example, halogen atoms, lower alkyl groups,hydroxyl group, lower alkoxy groups, lower alkoxycarbonyl groups,carbamoyl group and lower alkylcarbamoyl groups. The position of eachsubstituent and the position of each bond may be any position Asspecific examples of the substituted or unsubstituted heterocyclic alkylgroup, there can be mentioned 2-pyridylmethyl group, 4-pyridylmethylgroup, 2-fluoropyridylmethyl group, 2,4-difluoropyridylmethyl group,4-chloropyridylmethyl group, 2-bromopyridylmethyl group,2-iodopyridylmethyl group, 2-methylpyridylmethyl group,4-methylpyridylmethyl group, 2-hydroxypyridylmethyl group,2-methoxypyridylmethyl group, 2-carbamoylpyridylmethyl group,4-methylcarbamoylpyridylmethyl group, 3-pyridazylmethyl group,2-pyrimidylmethyl group, 2-pyrazinyl group, 2-(1,3,5-triazinyl)methylgroup, α-pyran-2-yl-methyl group, thian-2-yl-methyl group,1,4-dithian-2-yl-methyl group, 2-furylmethyl group,dioxofuran-2-yl-methyl group, 2-thienylmethyl group, oxazol-2-yl-methylgroup, isoxazol-3-yl-methyl group, thiazol-2-yl-methyl group,isothiazol-3-yl-methyl group, benzofuran-2-yl-methyl group,coumaran-2-yl-methyl group, benzothiophen-2-yl-methyl group,benzothiophen-3-yl-methyl group, benzothiophen-4-yl-methyl group,benzothiophen-5-yl-methyl group, benzothiophen-6-yl-methyl group,benzothiophen-7-yl-methyl group, indolin-1-yl-methyl group,benzoxazol-2-yl-methyl group, benzthiazol-2-yl-methyl group,4-fluorobenzothiazol-2-yl-methyl group, 5-fluorobenzothiazol-2-yl-methylgroup, 6-fluorobenzothiazol-2-yl-methyl group,7-fluorobenzothiazol-2-yl-methyl group, benzothiazol-4-yl-methyl group,benzothiazol-5-yl-methyl group, benzothiazol-6-yl-methyl group,benzothiazol-7-yl-methyl group, 2H-chromen-2-yl-methyl group,4H-chromen-2-yl-methyl group, quinolin-2-yl-methyl group,quinazolin-2-yl-methyl group, quinoxalin-2-yl-methyl group,1-(2-pyridyl)ethyl group, 1-(2-fluoropyridyl)ethyl group,1-(2,4-difluoropyridyl)ethyl group, 1-(2-chloropyridyl)ethyl group,1-(2-bromopyridyl)ethyl group, 1-(2-iodopyridyl)ethyl group,1-(2-methylpyridyl)ethyl group, 1-(2-ethylpyridyl)ethyl group,1-(2,4-diethylpyridyl)ethyl group, 1-(2-hydroxypyridyl)ethyl group,1-(3-hydroxy-pyridyl)ethyl group, 1-(2-methoxypyridyl)ethyl group,1-(4-ethoxycarbonylphenyl)ethyl group, 1-(2-carbamoylpyridyl)ethylgroup, 1-(2-methylcarbamoylpyridyl)ethyl group, 1-(3-pyridazyl)ethylgroup, 1-(2-pyrimidyl)ethyl group, 1-(4-pyrimidyl)ethyl group,1-(2-pyrazinyl)ethyl group, 1-(2-(1,3,5-triazinyl))ethyl group, 1-(α-pyran-2-yl)ethyl group, 1-(β-pyran-2-yl)ethyl group,1-(β-pyran-3-yl)ethyl group, 1-(β-pyran-4-yl)ethyl group,1-(dioxan-2-yl)ethyl group, 1-(thian-2-yl)ethyl group,1-(1,4-dithian-2-yl)ethyl group, 1-(2-furyl)ethyl group,1-(oxolan-2-yl)ethyl group, 1-(dioxofuran-2-yl)ethyl group,1-(2-thienyl)ethyl group, 1-(oxazol-2-yl)ethyl group,i-(isoxazol-3-yl)ethyl group, 1-(thiazol-2-yl)ethyl group,1-(isothiazol-3-yl)ethyl group, 1-(benzofuran-2-yl)ethyl group,1-(coumaran-2-yl)ethyl group, 1-(benzothiophen-2-yl)ethyl group,1-(indolizin-1-yl)ethyl group, 1-(benzoxazol-2-yl)ethyl group,1-(benzothiazol-2-yl)ethyl group, 1-(4-fluorobenzothiazol-2-yl)ethylgroup, 1-(5-fluorobenzothiazol-2-yl)ethyl group,1-(6-fluorobenzothiazol-2-yl)ethyl group,1-(7-fluorobenzothiazol-2-yl)ethyl group, 1-(benzothiazol-4-yl)ethylgroup, 1-(benzothiazol-5-yl)ethyl group, 1-(benzothiazol-6-yl)ethylgroup, 1-(benzothiazol-7-yl)ethyl group, 1-(2H-chromen-2-yl)ethyl group,1-(4H-chromen-2-yl)ethyl group, 1-(quinolin-2-yl)ethyl group,1-(quinazolin 2-yl)ethyl group, 1-(quinoxalin-2-yl)ethyl group,2-(2-pyridyl)ethyl group, 2-(2-fluoropyridyl)ethyl group, 2-(2,4difluoropyridyl)ethyl group, 2-(2-chloropyridyl)ethyl group,2-(2-bromopyridyl)ethyl group, 2-(2-iodopyridyl)ethyl group,2-(2-methylpyridyl)ethyl group, 2-(4-ethylpyridyl)ethyl group,2-(2-hydroxypyridyl)ethyl group, 2-(2-methoxypyridyl)ethyl group,2-(2-ethoxycarbonylpyridyl)ethyl group, 2-(2-carbamoylpyridyl)ethylgroup, 2-(2-methylcarbamoylpyridyl)ethyl group, 2-(3-pyridazyl)ethylgroup, 2-(4-pyridazyl)ethyl group, 2-(4-pyrimidyl)ethyl group,2-(2-pyrazinyl)ethyl group, 2-(2-(1,3,5-triazinyl))ethyl group, 2-(α-pyran-2-yl)ethyl group, 2-(β-pyran-2-yl)ethyl group,2-(β-pyran-3-yl)ethyl group, 2-β-pyran-4-yl)ethyl group,2-(thian-2-yl)ethyl group, 2-(1,4-dithian-2-yl)ethyl group,2-(2-furyl)ethyl group, 2-(oxolan-2-yl)ethyl group,2-(dioxolan-2-yl)ethyl group, 2-(2-thienyl)ethyl group,2(oxazol-2-yl)ethyl group, 2-(isoxazol3-yl)ethyl group,2-(thiazol-2-yl)ethyl group, 2-(isothiazol-3-yl)ethyl group,2-(benzofuran-2-yl)ethyl group, 2-(coumaran-2-yl) ethyl group,2-(benzothiophen-2-yl)ethyl group, 2-(indolizin-1-yl)ethyl group,2-(benzoxazol-2-yl)ethyl group, 2-(benzothiazol-2-yl) ethyl group,2-(4-fluorobenzothiazol-2-yl)ethyl group,2-(5-fluorobenzothiazon-2-yl)ethyl group, 2-(6-fluorobenzothiazol-2-yl)ethyl group, 2-(7-fluorobenzothiazol-2-yl)ethyl group,2-(benzothiazol-4-yl)ethyl group, 2-(benzothiazol-5-yl)ethyl group,2-(benzothiazol-6-yl)ethyl group, 2-(benzothiazol-7-yl)ethyl group,2-(2H-chromen-2-yl)ethyl group, 2-(4H-chromen-2-yl)ethyl group,2-(quinolin-2-yl)ethyl group, 2-(quinazolin 2-yl)ethyl group and2-quinoxalin-2-yl)ethyl group.

Then, description is made on the process of the present invention.

First, description is made on the reaction of the amino acid representedby the general formula (1) with the halogenated carbonic acid esterrepresented by the general formula (2).

In the reaction, an amino acid represented by the general formula (1) isdissolved in water in the form of its alkali metal salt and is reacted,in the presence of the water, with a halogenated carbonic acid esterrepresented by the general formula (2) to convert the amino group of theamino acid represented by the general formula (1) into an amide.

In the reaction, the amino acid represented by the general formula (1)used as a raw material, can be any compound represented by the generalformula (1). When the compound has one or more asymmetric carbon atoms,the compound may be a single pure optical isomer, or a mixture (e.g. aracemic modification) of any proportions of individual optical isomers,or a diastereomers mixture. In the reaction, the configuration of theraw material is kept even after the completion of the reaction. Asspecific examples of the amino acid represented by the general formula(1), there can be mentioned glycine, alanine, β-alanine, valine,norvaline, leucine, norleucine, isoleucine, serine, threonine,methionine, phenylalanine, tyrosine, γ-aminobutyric acid, anthranilicacid and p-aminobenzoic acid. Incidentally, the amino acid representedby the general formula (1) is known, or can be produced by, for example,the process described in “JIKKEN KAGAKU KOZA (4TH EDITION) compiled byTHE CHEMICAL SOCIETY OF JAPAN, Vol. 22, ORGANIC SYNTHESIS IV, ACID.AMINOACID.PEPTIDE, PP. 193-309”.

The halogenated carbonic acid ester represented by the general formula(2), used in the reaction can be any compound represented by the generalformula (2). As specific examples of the halogenated carbonic acid esterrepresented by the general formula (2), there can be mentionedchlorocarbonic acid esters such as methyl chlorocarbonate, ethylchlorocarbonate, n-propyl chlorocarbonate, isopropyl chlorocarbonate,n-butyl chlorocarbonate, isobutyl chlorocarbonate, n-pentylchlorocarbonate, isopentyl chlorocarbonate, neopentyl chlorocarbonate,cyclohexyl chlorocarbonate and the like. Incidentally, the halogenatedcarbonic acid ester represented by the general formula (2) is known, orcan be produced by, for example, the process described in “Lasurewskii;Forostjam et al., 29 (1959) 3498; engl. Ausg., etc.”.

In the reaction, the use amount of the halogenated carbonic acid esterrepresented by the general formula (2) is 0.8 to 10 moles, preferably1.0 to 3.0 moles per mole of the amino acid represented by the generalformula (1). Water used as a reaction solvent is used in an amount of0.01 to 10 liters, preferably 0.1 to 5 liters per mole of the amino acidrepresented by the general formula (1).

In the reaction, the amino acid represented by the general formula (1)is beforehand made into an aqueous solution of its alkali metal salt,using an aqueous solution of an alkali metal hydroxide such as sodiumhydroxide, potassium hydroxide or the like. Specifically, this can bedone by dissolving the amino acid represented by the general formula (1)in an aqueous solution of an alkali metal hydroxide. In this case, theaqueous solution of an alkali metal hydroxide is used in such an amountthat the alkali becomes 1 to 10 moles, preferably 2 to 3 moles per moleof the amino acid represented by the general formula (1).

In the reaction, to the aqueous solution of the alkali metal salt of theamino acid represented by the general formula (1) is added a halogenatedcarbonic acid ester represented by the general formula (2). Thehalogenated carbonic acid ester represented by the general formula (2)is preferably added dropwise at −20 to 80° C., preferably 0 to 50° C. inorder to suppress the decomposition of the halogenated carbonic acidester.

The reaction after the dropwise addition of the halogenated carbonicacid ester represented by the general formula (2) is conducted at −20 to80° C., preferably 0 to 50° C. for 10 hours or less, preferably 2 hoursor less.

Next, description is made on the reaction of the thus-produced amidecompound represented by the general formula (3) with a halogenatedcarbonic acid ester represented by the general formula (4), forproduction of a mixed acid anhydride represented by the general formula(5).

In this reaction, the amide compound represented by the general formula(3) is reacted with a halogenated carbonic acid ester represented by thegeneral formula (4) in water or a water-organic solvent mixture, toproduce a mixed acid anhydride represented by the general formula (5).

In the reaction, as the amide compound represented by the generalformula (3), used as a raw material, the reaction mixture obtained inthe previous reaction between the amino acid represented by the generalformula (1) and the halogenated carbonic acid ester represented by thegeneral formula (2) can be used per se in the same reactor and thereaction product obtained in the previous reaction need not be isolated.

The halogenated carbonic acid ester represented by the general formula(4), used in the reaction can be any compound represented by the generalformula (4). As specific examples of the halogenated carbonic acid esterrepresented by the general formula (4), there can be mentionedchlorocarbonic acid esters such as methyl chlorocarbonate, ethylchlorocarbonate, n-propyl chlorocarbonate, isopropyl chlorocarbonate,n-butyl chlorocarbonate, isobutyl chlorocarbonate, n-pentylchlorocarbonate, isopentyl chlorocarbonate, neopentyl chlorocarbonate,cyclohexyl chlorocarbonate and the like; and bromocarbonic acid esterssuch as methyl bromocarbonate, ethyl bromocarbonate, n-propylbromocarbonate, isopropyl bromocarbonate, n-butyl bromocarbonate,isobutyl bromocarbonate, n-pentyl bromocarbonate, isopentylbromocarbonate, neopentyl bromocarbonate, cyclohexyl bromocarbonate andthe like. The use amount of the halogenated carbonic acid esterrepresented by the general formula (4) can be 0.5 to 10 moles,preferably 0.8 to 2.0 moles per mole of the amino acid represented bythe general formula (1) used as a raw material.

In carrying out the reaction, the aqueous solution of the alkali metalsalt of the amide compound represented by the general formula (3) is, asnecessary, neutralized with an acid such as hydrochloric acid, sulfuricacid or the like. Thereto may be added an organic solvent miscible orimmiscible with water, such as aromatic hydrocarbon (e.g. toluene,xylene, ethylbenzene or chlorobenzene), ester (e.g. methyl acetate orethyl acetate), ether (e.g. diethyl ether, tert-butyl methyl ether ordioxane), aliphatic hydrocarbon (e.g. pentane, n-hexane or cyclohexane),ketone (e.g. methyl isobutyl ketone), nitrile (e.g. acetonitrile),aprotic polar solvent (e.g. sulfolane, dimethylimidazolidinone,dimethylformamide or dimethylacet-amide). The use amount of the organicsolvent when used is 0.05 to 10 liters, preferably 0.1 to 5 liters permole of the amino acid represented by the general formula (1).

In the reaction, a halogenated carbonic acid ester represented by thegeneral formula (4) is added to a reaction system containing the amidecompound represented by the general formula (3). In this case, thehalogenated carbonic acid ester represented by the general formula (4)is preferably added dropwise at −20 to 100° C., preferably −5 to 30° C.in order to suppress the decomposition of the halogenated carbonic acidester.

The reaction after the dropwise addition of the halogenated carbonicacid ester represented by the general formula (4) is conducted at −20 to100° C., preferably −5 to 30° C. for not more than 10 hours, preferablynot more than 3 hours.

The reaction proceeds in a system free from any tertiary amine, asdescribed previously. However, use of a tertiary amine as a catalyst ispreferred for smooth proceeding of the reaction. As specific examples ofthe tertiary amine usable, there can be mentioned dimethylbenzylamine,triethylamine, tributylamine and pyridine. Dimethylbenzylamine ispreferred. The use amount of the tertiary amine is 0.001 to 5 moles,preferably 0.05 to 2 moles per mole of the amino acid represented by thegeneral formula (1).

Then, description is made on the production of an amic acid esterrepresented by the general formula (7) by reaction of the thus-producedmixed acid anhydride represented by the general formula (5) with anamine compound represented by the general formula (6).

In the reaction, the mixed acid anhydride represented by the generalformula (5) is reacted with an amine compound represented by the generalformula (6) in a system comprising water or a water-organic solventmixture, whereby is produced an amic acid ester represented by thegeneral formula (7), intended by the present invention process.

In the reaction, as the mixed acid anhydride represented by the generalformula (5), used as a raw material, the reaction mixture obtained inthe previous reaction between the amide compound represented by thegeneral formula (3) and the halogenated carbonic acid ester representedby the general formula (4) can be used per se in the same reactor andthe reaction product obtained in the previous reaction need not beisolated.

In the previous reaction, when an organic solvent immiscible with wateris used, the aqueous layer may be removed by phase separation, in orderto, for example, enable use of a reactor having a capacity as small aspossible per mole of the raw material. In that case, the reactionbetween the compound (5) and the compound (6) proceeds in the organicsolvent.

The amine compound represented by the general formula (6), used in thereaction can be any compound represented by the general formula (6).When the amine compound (6) has one or more asymmetric carbon atoms, thecompound may be a single optical isomer, or a mixture of any proportionsof individual optical isomers (e.g. a racemic modification), or amixture of diastereomers. An acid addition salt thereof may also beused. As specific examples of the amine compound represented by thegeneral formula (6) or its acid addition salt, there can be mentioned(R)-1-(6)-fluorobenzothiazol-2-yl)ethylamine,(S)-1-(6)-fluorobenzothiazol-2-yl)ethylamine,(thiophen-2-yl)methylamine, (R,S)-1-(4-methylfuran-3-yl)ethylamine,(R,S)-1-(5-methoxyisobenzofuran-6-yl)propylamine,(R,S)-1-(4-chloropyridin-2-yl)ethylamine, (R,S)-1-pyrazinylethylamine,(4,6-dimethoxypyrimidin-2-yl)methylamine,(R,S)-1-(2H-pyrrol-3-yl)ethylamine, pyrazinylmethylamine,(indol-1-yl)methylamine, (quinolizin-2-yl)methylamine,2-methoxycarbonylbenzylamine, 4-ethoxycarbamoylbenzylamine,4-carbamoylbenzylamine; inorganic acid salts of the above aminecompounds represented by the general formula (6), such as hydrochloride,sulfate, sodium hydrogensulfate salt, phosphate, sodiumdihydrogenphosphate salt, carbonate, sodium hydrogencarbonate salt andthe like; and organic acid salts of the above amine compoundsrepresented by the general formula (6), such as acetate, citrate,methanesulfonate, trifluoromethanesulfonate, benzenesulfonate,p-toluenesulfonate, p-chlorobenzenesulfonate and the like. The useamount of such a compound is 0.5 to 10 moles, preferably 0.5 to 2 molesper mole of the amino acid represented by the general formula (1).

Incidentally, for example, the above(R)-1-(6-fluorobenzothiazol-2-yl)ethylamine can be produced by adding acorresponding 2-aminothiophenol derivative alkali metal salt into anacid to reduce the pH of the salt to 6 or less and then reacting theresulting 2-aminothiophenol derivative with a corresponding aminoacid-N-carboxyanhydride (see Japanese Patent Application No.2000-100466).

When, in the reaction, the amine compound represented by the generalformula (6) is used in the form of its acid addition salt, the acidaddition salt is converted into a free amine compound represented by thegeneral formula (6) by adding an alkali into the reaction system. As thealkali used therefor, there can be mentioned, for example, sodiumhydroxide and potassium hydroxide. The alkali may be added into thereaction system as an aqueous solution containing 1 to 100%, preferably10 to 50% of the alkali. The use amount of the alkali is 1 mole or more,preferably 1 mole per mole of the acid addition salt of the aminecompound represented by the general formula (6).

The reaction can be conducted by adding an amine compound represented bythe general formula (6) to a system containing the mixed acid anhydriderepresented by the general formula (5), in a system comprising water ora water-organic solvent mixture, or in a system comprising an organicsolvent when, in the previous reaction, an organic solvent immisciblewith water is used and, after the previous reaction, the aqueous layeris removed by phase separation, and then stirring the resulting mixture.The temperature of the reaction is −20 to l100° C., preferably 0 to 50°C., and the period of the reaction is 10 hours or less, preferably 0.5to 5 hours.

After the completion of the reaction, the intended product of presentprocess, i.e. the amic acid ester represented by the general formula (7)is in dissolution in the organic phase of the reaction mixture.Therefore, the reaction mixture is subjected to phase separation by anordinary method, the separated organic phase is, as necessary, washedwith water and dried, then the organic solvent in the organic phase isdistilled off to isolate the intended product. Alternatively, thereaction mixture is not subjected to phase separation and is subjectedto distillation to remove the organic solvent contained in the reactionmixture and obtain an aqueous suspension of the intended product, andthe suspension is filtered to isolate the intended product.

The process of the present invention is described more specificallybelow by way of a reference example and examples.

REFERENCE EXAMPLE

40 ml of water and 30 g (0.296 mole) of 36% hydrochloric acid wereplaced in a 300-ml reaction flask and cooled to 3° C. Thereto wasdropwise added, at 2 to 5° C. with stirring, 48.0 g (0.056 mole) of anaqueous solution of a potassium metal salt of2-amino-5-fluorothiophenol, followed by stirring for 1 hour. Theresulting mixture had a pH of 5.23. Thereto were added 9.7 g (0.051mole) of p-toluenesulfonic acid monohydrate and 15 ml oftetrahydrofuran, followed by stirring for 30 minutes. Then, 8.1 g (0.055mole) of D-alanine-N-carboxyanhydride (purity: 78.3%) was added at 0° C.Aging was conducted at 15 to 20° C. for 18 hours. The resulting crystalswere collected and dried at 60° C. to obtain 16.6 g of[2-(6-fluorobenzothiazolyl)]ethylamine.4-methylbenzenesulfonate (purity:93.5%). The yield was 82.8% relative to the potassium metal salt of2-amino-5-fluorothiophenol.

Example 1

16.1 g (0.092 mole) of 23% sodium hydroxide, 10 ml of water and 4.7 g(0.04 mole) of L-valine were placed in a 300-ml reaction flask, andstirred at room temperature for 30 minutes. Thereto was dropwise added5.9 g (0.048 mole) of isopropyl chlorocarbonate at room temperature,followed by stirring for 1 hour. The resulting mixture was neutralizedwith concentrated hydrochloric acid. Thereto were added 100 ml oftoluene and 0.06 g (0.0004 mole) of N,N-dimethylaminobenzylamine. Then,4.7 g (0.038 mole) of isopropyl chlorocarbonate was added dropwise atroom temperature, followed by stirring for 1 hour. Thereafter, there wasadded 14.0 g (0.038 mole) of(R)-1(6-fluorobenzothiazol-2-yl)]ethylamine.4-methylbenzenesulfonate(purity: 97.4%, optical purity: 99.2% ee) produced according to theabove Reference Example. Further, 15.2 g (0.038 mole) of 10% sodiumhydroxide was added dropwise at room temperature, followed by stirringfor 2 hours. 50 ml of water was added; the resulting mixture was heatedto 70° C. and subjected to phase separation; the toluene layer waswashed with 50 ml of hot water and subjected to solvent removal toobtain 13.0 g (yield: 89.7%) of isopropyl[(S)-1-[(R)-1-(6-fluorobenzothiazol-2-yl)ethylcarbamoyl]2-methylpropyl]carbamate(purity: 97.2%, the proportion of formed intended substance in fourdiastereomers: 99.2%).

Example 2

16.1 g (0.092 mole) of 23% sodium hydroxide, 10 ml of water and 4.7 g(0.04 mole) of L-valine were placed in a 300-ml reaction flask, andstirred at room temperature for 30 minutes. Thereto was dropwise added5.9 g.(0.048 mole) of isopropyl chlorocarbonate at room temperature,followed by stirring for 1 hour. The resulting mixture was neutralizedwith concentrated hydrochloric acid. Thereto were added 50 ml of tolueneand 0.06 g (0.0004 mole) of N,N-dimethylaminobenzylamine. Then, 4.7 g(0.038 mole) of isopropyl chlorocarbonate was added dropwise at roomtemperature, followed by stirring for 1 hour. Thereafter, there wasdropwise added a solution of 7.5 g (0.038 mole) of(R)-1-(6-fluorobenzothiazol-2-yl)ethylamine (purity: 98.3%, opticalpurity: 99.0% ee) dissolved in 50 ml of toluene, produced according tothe above Reference Example, followed by stirring at room temperaturefor 2 hours. 50 ml of water was added; the resulting mixture was heatedto 70° C. and subjected to phase separation; the toluene layer waswashed with 50 ml of hot water and subjected to solvent removal toobtain 13.4 g (yield: 92.4%) of isopropyl[(S)-1-[(R)-1(6-fluorobenzothiazol-2-yl)ethylcarbamoyl]-2-methylpropyl]carbamate(purity: 96.3%, the proportion of formed intended substance in fourdiastereomers: 98.5%).

Industrial Applicability

The present invention provides a process for producing an amic acidester useful as an intermediate for production of agrochemicals, easilyindustrially at a low cost. The present process proceeds even in thepresence of water and can be carried out in one pot (one reactor) asnecessary.

When the raw materials used [e.g. the amino acid represented by thegeneral formula (1) and the amine compound represented by the generalformula (6)] are optically active compounds, an optically active amicacid ester can be synthesized without giving rise to a substantialreduction in the optical purities of the raw materials and thereforewith their optical purities being retained. Therefore, the presentprocess can be used also for production of an intermediate for opticallyactive agrochemicals. Thus, the present process has a very highindustrial value.

What is claimed is:
 1. A process for producing an amic acid esterrepresented by the following general formula (7):

(wherein A is a substituted or unsubstituted lower alkylene group, asubstituted or unsubstituted cycloalkylene group, a substituted orunsubstituted arylene group, a substituted or unsubstitutedcycloalkylalkylene group or a substituted or unsubstituted aralkylenegroup; R₁ is a substituted or unsubstituted lower alkyl group, asubstituted or unsubstituted cycloalkyl group, a substituted orunsubstituted aryl group, a substituted or unsubstituted cycloalkylalkylgroup, a substituted or unsubstituted aralkyl group, a substituted orunsubstituted heterocyclic group or a substituted or unsubstitutedheterocyclic alkyl group; and R₃ is a hydrogen atom or a lower alkylgroup), which process comprises reacting, in the presence of water, anamino acid represented by the following general formula (1):

 (wherein A has the same definition as given above) with a halogenatedcarbonic acid ester represented by the following general formula (2):

 (wherein R₁ has the same definition as given above and X is a halogenatom) to form an amide compound represented by the following generalformula (3):

 (wherein A and R₁ have the same definitions as given above), thenreacting the amide compound with a halogenated carbonic acid esterrepresented by the following general formula (4):

 (wherein R₂ is a substituted or unsubstituted lower alkyl group, asubstituted or unsubstituted cycloalkyl group, a substituted orunsubstituted aryl group, a substituted or unsubstituted cycloalkylalkylgroup, a substituted or unsubstituted aralkyl group, a substituted orunsubstituted heterocyclic group or a substituted or unsubstitutedheterocyclic alkyl group; and X is a halogen atom) to form, in thesystem, a mixed acid anhydride represented by the following generalformula (5):

 (wherein A, R₁ and R₂ have the same definitions as given above), andreacting the mixed acid anhydride with an amine compound represented bythe following general formula (6):

 (wherein R₃ has the same definition as given above and Het is asubstituted or unsubstituted heterocyclic group).
 2. A process forproducing an amic acid ester, set forth in claim 1, wherein the aminoacid represented by the general formula (1) is dissolved in water andreacted with the halogenated carbonic acid ester represented by thegeneral formula (2).
 3. A process for producing an amic acid ester, setforth in claim 1, wherein the reaction of the amide compound representedby the general formula (3) with the halogenated carbonic acid esterrepresented by the general formula (4) is conducted in a reaction systemcomprising water or a water-organic solvent mixture.
 4. A process forproducing an amic acid ester, set forth in claim 1, wherein the reactionof the mixed acid anhydride represented by the general formula (5) withthe amine compound represented by the general formula (6) or its salt isconducted in a reaction system comprising water or a water-organicsolvent mixture.
 5. A process for producing an amic acid ester, setforth in claim 1, wherein all the steps are conducted in one pot (onereactor).
 6. A process for producing an amic acid ester, set forth inclaim 1, wherein the amino acid represented by the general formula (1)is valine and the chlorocarbonic acid ester represented by the generalformula (2) is isopropyl chlorocarbonate.
 7. A process for producing anamic acid ester, set forth in claim 6, wherein all the steps areconducted in one pot (one reactor).
 8. A process for producing an amicacid ester, set forth in claim 1, wherein the amino acid represented bythe general formula (1) is an optically active valine and the aminerepresented by the general formula (6) is an optically active1-(6-fluorobenzothiazol-2-yl)ethylamine.
 9. A process for producing anamic acid ester, set forth in claim 8, wherein all the steps areconducted in one pot (one reactor).